16-alkyl steroids and process of preparing



Patented Mar. 11, 1952 UNITED STATES PATENT OFFICE 2,588,391 16-ALKYLSTEROIDS AND PROCESS OF PREPARING Percy L. Julian, Maywoodfand Edwin W.Meyer and Helen Printy, Chicago, Ill., assignors to The Glidden Company,Cleveland, Ohio, a, corporation of Ohio Serial No. 749,887

This invention relates to 16-alkylated compounds of the androsteneseries, and particularly to 16-methyldehydroisoandrosterone,IG-methylenedehydroisoandrosterone and 16methyltest0-.

sterone.

It has been fairly well established that testolsterone is rather rapidlydestroyed in the liver ably undergoes hydrolysis slowly in the body. andin this way the testosterone is more slowly released.1"1-methyltestosterone, being normally foreign to the body, issupposedly more slowly metabolized.

It is conceivable that the presence of a methyl group in theIii-position might not only allow of maintenance of androgenicproperties, but might sustain the testiculoid activity in an even morefavorable manner than the above mentioned derivatives. lhe addedhindrance of a methyl 16 Claims. (01. zed-397.4)

group in the lfi-position might particularly favor slow saponificationof a 17-ester in vivo.

In addition to the testiculoid activity these androgenic materials alsofrequently haveother efiects which may not be desirable. Thus 17- methyltestosterone has the effect of causing an undesirable enlargement of theprostate. An androgenic material which would possess these undesirableproperties ina' lesser degree would be highly useful.

It is accordingly an object of the present in- I.lfi-dimethylaminomethyldehydroisoandrosterone No Drawing. ApplicationMay22, 1947 2 vent-ion to provide new compounds of the androsteneseries.

It is a further object of the present invention to provide newderivatives of testosterone.

Another object is to provide new androgenic materials of improvedproperties.

An additional object is to provide a process for preparing the newcompounds of the present invention.

Other objects will be apparent to those skilled in the art from thefollowing description. According to the present inventiontl'ie Mannichbases of dehydroisoandrosterone are treated to split' off an amine, withthe formation of a lit-methylene derivative. Thismay preferably beaccomplished by heating the ld-aminomethyl compounds-in thepre'sence ofan acid anhydride or an alkali. Partialhydrogenation of the methylene,derivative leads first to the lG-methyl compound,, and more. completehydrogenation results in reduction of the l'l-keto group tothe alcohol.Esterification of the 17-OHgroup gives an-ester linkage which is slow tohydrolyze, the Iii-methyl group apparently increasing the sterichindrance. This may be an advantage-where thereis already an ester,linkage atthe 3-position since partial hydrolysis would lead to a goodyield of the B-hydroxy-ll-acyl compounds. The B-hydroxy-l'Y-acylcompound may then be oxidizedto the=3-keto17-acyl compound. When desiredthe 3-keto-1'T-acyl compound may then be hydrolyzed to 16 -methyltestosterone. These reactions may be represented by the followingequations; where Ris a hydrocarbon radical. 0H5 CH5 O a I AcO II.l6-methylenedehydroisoandrosterone acetate CH: 0 Ha In.lfi-methyldehydroisoandrosterone acetate I T esterification C H] H 0 C OR O C O R CH1; CH:

CH: QH:

Partial w A00 hydrolysis 4 HO V. lfi-methyl-A -andtostene- VI.lfi-methyl-A -androstene- 3,1] diohflacetato-ll-ester 3,17 di0l-17'estcr1 oxidation 0 H1 i C H! 0 C 0 R CH! H:

0 HI C H:

hydrolysis VIII. lfi-methyltestosterone It is not essential that anesterifying agent be present during the splitting off of the amine.However, subsequent esterification of the 17 -OH group results inesterification of an OI-I group in the 3-position. It would not bedesirable to put a difficultly hydrolyzable group in both the 3 and 17positions and,- therefore, if such a group were used forl'7-esterification, the preferred course would be to have an easilyhydrolyzable group in the 3 position. For this reason it may bedesirable to acylate in the 3 position prior to esterification of the17-OH group. This makes the deamination procedure with an acylationmixture like acetic acid-acetic anhydride a preferred procedure incertain cases. This selective esterification may, of course, be effectedat any time prior to the esterification-of the 17-OH group. The

lfi-methylene derivative may also be prepared by removal of the elementsof an aliphatic amine from the Mannich base of dehydroisoandrosteronethrough the use of sodium ethoxide or similar alkaline reagent.

The lfi-aminomethyl compounds may be prepared fromdehydroisoandrosterone by the Mannich reaction, which reaction comprisesheating ketones with formaldehyde and an amine under appropriateconditions. The reaction may be i l lustrated by the following equation:

where R is a hydrocarbon or a substituted hydro- VII.lfrmethyltestosterone ester E :rample I .1 6 -diinethijlaminomethyldeh1ldroisoandrosterone C Ha CH: Ha

' sion was made alkaline with cold dilute sodium carbonate solution andexhaustively extracted with ether. After washing the ether solution withwater to free it'of alkali, it was dried and concentrated. From theconcentrated ethereal solution a white solid crystallized. The solidweighed 2.5 g. and melted at 158168 0., dec. Recrystallized from etherpetroleum ether (B. P.

' 35-60 C.) gave needles melting at l'73174.5 C.

carbon radical, and R', R", R' and R"" may be hydrogen or hydrocarbonradicals. In the case of the ketones and the amines the carbonyl groupaswell as the nitrogen may be a part ofa cyclic system, such as incyclohexanone and piperidine,

respectively. 7 r v The following examples are illustrative of preferredmodes of carrying out the present inven- A tion: g V

dec.

Example II .--1 6-methylenedehydroisoandrosterone acetate 0 CH3 II Asolution of g. of lfi-dimethylaminomethyldehydroisoandrosterone in cc.of acetic acid and25 cc. of acetic anhydride was heated on the steambath for two hours. The majority of the solvent was then removed inpartial vacuum at steam bath temperature and water was added to the mushof solid material. The mixture was extracted with ether. The etherealextract was washed with 10% aqueous sodium hydroxide solution followedby water. concentrated and the product crystallized by addition ofpetroleum ether (B. P. -60 C.). The petroleum ether was added as theether was removed. There resulted 8.0 g. of white crystalline materialmelting at l-165 C.

Example III. 16-methyldehyclroisoandrosterone acetate CHs OH: I

AcO

A solution of 2.5 g. of 16-methylenedehydroiso-' androsterone acetate incc. of absolute ethanol was reduced in the presence of Raney nickelcatalyst with hydrogen at one atmosphere pressure and 30 C. The reactionwas stopped after one mole equivalent of the gas was absorbed. Thecatalyst was separated and the ethanol removed in vacuo. Thecrystalline, white solid residue was crystallized from ether-petroleumether (B. P. 35- 60 C.), 1.6 g., M. P. 137-143 C. Severalrecrystallizations from methanol gave the pure product,16-methyldehydroisoandrosterone acetate, as heavy needles melting at144-146 C.

This ketone formed a semicarbazone derivative melting at 243-2 l5 C.with decomposition.

Example IV.---1 6 -methyZ-5 -andr0stene-3,1 7 -di0l ,3-acetate-1 7-benz0ate 00o O H: I

TOE:

A solution of 3.4. g. of the methylene compound of Example II inpurified ethanol (60 cc.) was reduced with fresh Raney nickel catalystat 4 atmos. pressure and 2530 C. The catalyst was separated and thesolution combined with that of a similar hydrogenation of 3.4 g. ofmethylene compound. Ethanol was removed in partial vacuum at steam bathtemperature. The

last traces of ethanol were removed by addition removal of ether, theresidue was steam dis- The dry solution was tilled. 'The remainingmaterial was taken up in ether and washed with dilute sodium hydroxidesolution and water. Crystallization from methanol of the residue fromthe dried ethereal solution gave. 4.0 g. of the acetate-benzoate meltingat -147 C. Recrystallization from methanol gave glistening white platesmelting at 148-151 C.

Example V.16-methyl-5-andr0stene-3,17-diol- 3,17-diacetate AGO In afashion similar to that of Example IV, the diacetate was prepared. Inthis instance after removal of solvent from the reduction solution, theresidue was acetylated with acetic anhydride-acetic acid mixture. Thediacetate when crystallized from petroleum ether (B. P. 35-60 C.)existed as white plates melting at -1775 C.

Example VI .1 6 -methyZ-5-androstene-3,1 7 -dzol- 1 7 -benzoate 1 OCOCH3 To a solution of 4.0 g. of the acetate-benzoate of Example 1V in 200cc. of methanol, there was added a solution of 0.8 g. of potassiumhydroxide in 7.0 cc. of water and 33 cc. of methanol. The resultingsolutionwas refluxed for 25 minutes and then concentrated in vacuo overa steam bath. The last of the concentration was accomplished with steamturned off. The concentration was continued until a goodly amount ofcrystalline solid had separated. This was filtered and washed with coldmethanol-3.1 g. of glistening plates melting at 152-154 C.

Example VHS-1 6 -methyl-5-androstene-3,1 7

- diol-17-acetate The diacetate of Example V was also hydrolyzedaccording to the directions of Example VI. There resulted thel'l-acetate, glistening white plates, melting at 164.5--168.5 C.

Example VIII.-1'6-mthyltestostermze benzoate A solution of 3.0 g. of themonobenzoate from Example VI in 50 cc. of chloroform was brominated with1.14 g. of bromine in 10 cc. chloroform. The solvent was removed invacuo and the residue dissolved in 2'75 cc. of glacial acetic acid. Anoxidizing mixture composed of 1.2 g. of chromic acid, 14 cc. of waterand 35 cc. of acetic acid was added. The brown solution was allowed tostand at room temperature for two hours. After addition of 4 cc. 3 Nsulfuric acid in 17 cc. of acetic acid and then 14 cc. of methanol (todecompose excess 0103), the solution was debrominated under CO2 with 95cc. of 1 molar chromous chloride solution in 90 cc. of acetic acid. Thesolution was allowed, to stand overnight, concentrated in vacuo, dilutedwith water and extracted with ether. The extract was washed with water,dilute sodium hydroxide solution and water. It was dried andconcentrated and the product crystallized from etherpetroleum ether (B.P. 3560 C.). There re,- sulted 2.0 g. of white prisms, M. P. 223-225.5C.

Example IX.1G-methyltestosterone on CH3 The keto-benzoate (1.5 g.) ofExample VIII was hydrolyzed with 0.8g. of potassium hydroxide in 5 cc.water and 50 cc. of methanol by refluxing eleven hours; After dilutionwith water the product was extracted with ether. From the washed anddried ether solution, the crude methyltestosterone was separated byconcentration and chilling. It melted at 175-182 C. Recrystallizationfrom acetone gave prisms melting at 182-185 C. 1

Example X.i6-methyliestosterone acetate CH A0 A solution of 6.92 g. ofl6-methyl-5-androstene-3,17-dio1-1'7-acetate in '75 cc. ofmethylenedichloride was brominated in the cold with 3.2 g. of bromine incc. of methylene dichloride. The solvent was removed in vacuo and thewhite, solid residue dissolved in 500 cc. of glacial acetic acid. Afteradding a solution of 3.5 g. of chromic acid in -00. oi waterand cc.

8 of glacial acetic acid, the mixture was allowed to stand at roomtemperature for two and onehalf hours. The excess oxidizing agentwas thn destroyed by the addition of 10 cc. 3 N sulfuric acid, 30 cc. ofglacial acetic acid and 30 cc. of methanol. The green solution was thendebrominated under CO2 with 160 cc. of ,1 molar chromous chloridesolution in 160 cc. of glacial acetic acid. After three hours, thesolution was concentrated, diluted with water and extracted with ether.The ether solution was washed with water, dilute sodium hydroxidesolution and water. After removal of ether, the product was crystallizedfrom ether-petroleum ether. The 16-methyltestosterone acetate formedprisms "melting at 154-461 C.

It is to be understood that the foregoing ex-' amples are merelyillustrative and that various modifications ma be made therein withoutdeparting from the invention. Thus any Mannich base ofdehydroisoandrosterone may be used as starting material. Thedimethylaminc-methyl compound is to be preferred in most cases where itis to be made as a starting material for the present invention since theyields are good. However, other Mannich bases may be used such as thoseof diethylamino, piperidine, etc. The procedures for making the Mannichbases, such as is illustrated by Example I, may be used for preparingthe starting materials of the present invention.

Also other esters than those illustrated in the examples may beprepared. As indicated above, however, it is generally preferred to havean ester group in the 17 position which is more difficultly hydrolyzedthan the one in the 3 position. This is not essential, however, as isshown by Example VII. In certain cases it may be desirable to have adifferent ester group in the l6-methyltestosterone ester than was usedin the preparation. In such cases the original ester may be hydrolyzedand the resulting l6-methyltestosterone re-esterified with the desiredesterifying agent. Other known means may be emplayed for oxidizing the3OH group to the keto group.

Reference is made to our co-pending application, Serial No. 747,886,filed concurrently herewith, now Patent No. 2,562,194.

Having described the invention, what claimed is:

1. The process which comprises removing the elements of an aliphaticamine from a Mannich base of dehydroisoandrosterone to form a 16-methylene derivative of dehydroisoandrosterone, and hydrogenating saidlfi-methylene derivative using a Raney nickel catalyst.

2. The process of claim 1 in which 1 mole of hydrogen is added to eachmole of the 16-methylene derivative.

3. The process of claim 1 in which 2 moles of hydrogen are added to eachmole of the 16- methylene compound.

4. The process of claim 1 in which the removal of the elements of analiphatic amine is carried out by heating in a mixture of glacial aceticacid and acetic anhydride.

5. The process which comprises removing the elements of an aliphaticamine from a Mannich base of dehydroisoandrosterone to form a 16-methylene derivative of dehydroisoandrosterone, hydrogenating said16-methylene derivative with 2 moles of hydrogen for each mole of the16- methylene derivative using a Raney nickel catalyst, forming adi-ester of the hydrogenated 9 compound, partially hydrolyzing thedi-ester to free the 3-OH group, and oxidizing the 3-OH group to a ketogroup.

6. The process which comprises removing the elements of an aliphaticamine from a Mannich base of dehydroisoandrosterone to form a 16-methylene derivative of dehydroisoandrosterone, hydrogenating said16-methylene derivative with 2 moles of hydrogen for each mole of the16- methylene derivative using a Raney nickel catalyst, forming adi-ester of the hydrogenated compound, partially hydrolyzing thedi-ester to free the 3OH group, oxidizing the 3-OH group to a keto groupand hydrolyzing the resulting keto-ester to form 16-methyl testosterone.

'7. The process which comprises removing the elements of an aliphaticamine from a Mannioh base of dehydroisoandrosterone by heating in amixture of glacial acetic acid and acetic anhydride to form a,iii-methylene derivative of dehydroisoandrosterone.

8. The process which comprises heating 16-dimethylaminomethyldehydroisoandrosterone in a mixture of glacial aceticacid and acetic anhydride, hydrogenating the resultingIG-methylene-dehydroisoandrosterone acetate to 16-methy1-A-androsten-3,17-diol 3-acetate, esterifying the 17 hydroxyl group,partially hydrolyzing the resulting di-ester to the 3-hydroxy compound,and oxidizing the 3OH group thus formed to a keto group.

9. The process of claim 8 in which the remainin ester linkage in the17-position of the 3-keto compound is hydrolyzed to form 16-methyl-testosterone.

10. Derivatives of dehydroisoandrosterone acetate having as a solesubstituent on the dehydroisoandrosterone nucleus a hydrocarbon radicalattached to the 16-carbon atom of the nucleus, said hydrocarbon radicalconsisting of a single carbon atom bonded only to the 16-carbon atom ofthe nucleus and to hydrogen.

11. lfi-methyl androstene compounds having in the l'l-position an RCOO-group in which R is a hydrocarbon radical of less than 7 carbon atomsand in which the double bond of the androstene nucleus involves thenumber 5 carbon atom, said compounds being further characterized in thatthere is an oxygen containing radical molecular weight which is lessthan 18 attached through the oxygen thereof to the number 3 carbon atomof the androstene nucleus.

12. 16-methyl-A -androstene compounds having in the 3-position an RCOO-group in which R is a hydrocarbon radical of less than 7 carbon atoms,said compounds being further characterized in that there is an oxygencontaining l radical the molecular weight of which is less than 18attached through the oxygen thereof to the number 17 carbon atom ofnucleus.

13. 16-methyl testosterone. 14. Compounds of the general formula O OH:

wherein :n is selected from the group consisting of --OH and RCOO-wherein R is a hydrocarbon radical of less than 7 carbon atoms, and :yis selected from the group consisting of and =03,

15. Compounds of the general formula wherein R is a hydrocarbon radicalof less than 7 carbon atoms.

16. 16-methyl-5-androstendiol-3,1'7.

PERCY L. JULIAN.

EDWIN W. MEYER.

HELEN PRINTY.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS

1. THE PROCESS WHICH COMPRISES REMOVING THE ELEMENTS OF AN ALIPHATICAMINE FROM A MANNICH BASE OF DEHYDROISOANDROSTERONE TO FORM A16METHYLENE DERIVATIVE OF DEHYDROISOANDROSTERONE, AND HYDROGENATING SAID16-METHYLENE DERIVATIVE USING A RANEY NICKEL CATALYST.